The protozoan parasite Toxoplasma gondii infects all nucleated cells and establishes life-long chronic infections in virtually any warm-blooded vertebrate. Eliminating the ability of this parasite to establish chronic infections in humans and animals is central to controlling its pathogenesis, however, there is currently no human vaccine or drug capable of doing this. Our lab has identified a large superfamily of >182 SRS protein adhesins that are essential for 1) entry into host cells and 2) regulating host immunity in order to establish chronic infections. The SRS proteins are regulated in a development-specific manner, and we showed by gene-knockout studies that four of these antigens expressed by the tachyzoite stage are critical virulence factors: SRS29B, SRS29C, SRS34A, and SRS57. SRS57 is a pivotal adhesin required for establishing infection, whereas SRS29B, SRS29C, and SRS34A are primarily immunomodulating factors that elicit strong immunity in all infected hosts. We recently produced parasite strains deficient in the expression of SRS29B, SRS34A or both SRS29B and SRS34A. Srs29B- strains were less pathogenic in mice, had minimal disruption of their thymic architecture and produced substantially less IFN-g, in contrast to wild type parasites. Our results suggest that SRS29B is a critical virulence factor and that mice die from parasite burden and severe immune pathology dependent on SRS29B expression. Current investigations are testing whether collapse of regulatory T and B cells during acute ileitis is dependent on SRS29B. Srs34A- strains possessed an invasion defect, and were less virulent in murine infections. Importantly, Srs29B-Srs34A- doubly deficient parasites possessed no invasion defect, had upregulated expression of SRS29C and were severely attenuated during in vivo infection. Previously, we identified that the majority of mouse virulent Toxoplasma strains poorly express SRS29C, whereas all avirulent strains are high expressors. We tested whether SRS29C expression level was sufficient to alter the mouse virulence phenotype. When expressed transgenically in a virulent strain at levels equivalent to those found in avirulent strains, the SRS29C transgenic strains were highly attenuated. These data suggest that SRS29C is a pivotal virulence factor and that expression level is a critical determinant governing the outcome of infection. We are currently investigating the molecular and cellular basis of SRS29C mediated alterations in Toxoplasma pathogenesis in the murine infection model. Our recent work in Plasmodium has established that the 12 member 6-Cys family of P. falciparum surface proteins, which facilitate invasion of hepatocytes (P52/P36) and promote male/female gamete recognition and fertilization (Pfs 230, 48/45) are structurally related to the SRS proteins. Understanding the structural basis and cellular receptors for host cell entry within this superfamily of SRS antigens, and the type of immunity induced during natural infections should lay the foundation for therapeutic interventions, either prophylactic or vaccine-based, to limit infectivity and induce sterilizing immunity against widespread zoonotic pathogens.